Process for ay-g-oxomorphinan
derivatives



United States Patent 0. F

3 Claims. oi. 260-285) The present invention relates to A' -6-oXomorphinan derivatives and production thereof.

In the term morphinan herein employed, there are included all the compounds having a fundamental structure representable by the following planar formula:

' wherein R represents a hydrogen atom, an acyl group such as lower alkanoyl (e.g. acetyl, propionyl, butyryl) or a lower alkyl group (e.g. methyl, propyl, butyl), R represents a hydrogen atom, an aryloxy group (e.g. phenyloxy, naphthyloxy) or a substituted aryloxy group (e.g. substituted phenyloxy, substituted napthyloxy) wherein the substituent is lower alkyl (e.g. methyl, ethyl, propyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy), nitro or amino and R represents a hydrogen atom, a lower alkyl group (e.g. methyl, ethyl, propyl) or an ar(lower)-alkyl group, e.g. benzyl, phenethyl) and shows various pharmacological activities such as analgesic activity and antitussive activity.

Accordingly, a basic object of the present invention is to embody the A' -6-oxomorphinan derivative of Formula 1. Another object of the invention is to embody the pharmacologically active A -6-oxomorphinan (I). A further object of the invention is to embody a process for preparing the A --oxomorphinan (I). These and other objects will be apparent to those conversant with the art to which the present invention pertains from the subsequent description.

When distinction is necessary,

The process of the present invention is illustratively represented by the following scheme:

wherein R, R and R' each has the same significance as designated above and R" represents a lower alkyl group (e.g. methyl, ethyl, propyl).

As the starting material, there may be used the optically active or racemic A -6-alkoxymorphinan of Formula II.

According to the process of the present invention, the starting A -6-alkoxymorphinan (II) is subjected to hydrolysis with the simultaneous transformation of the double bond to produce a mixture of the A' -6-oxomorphinan (cis) (Ia) and the A -6-oxomorphinan (trans) (Ib), if necessary, followed by isomerization of the latter (Ib) to the former (la). The hydrolytic transformation is accomplished by treating the A -6-alkoxymorphinan (II) with an acidic substance such as organic acid (e.g. acetic acid, oxalic acid), inorganic acid (e.g. hydrochloric acid, sulfuric acid, nitric aid) and acidic salts thereof (eg potassium bisulfate, sodium bisulfate) in a hydrous medium at room temperature (10 to 30 C.) or while heating. Although there is usuallyobtained a mixture of the A -6-oxomorphinan (cis) (Ia) and the A -6-oxomorphinan (trans) (Ib) as the product, either of the said two isomers can be predominantly prepared by regulating the concentration of the employed acidic substance. Generally speaking, the high concentration of the acidic substance results in the prevalent production of the A' -6-oxomorphinan (cis) (Ia), while the low'concentration causes the predominant production of the A' -6-oxomorphinan (trans) (lb). The isomerization of the A -6-oxornorphinan (trans) (Ib) to the A"-6-oxomorphinan (cis) (la) is executed by treating the former with a high concentration of the said acidic substance in a hydrous medium at room temperature (10 to 30 C.) or while heating. In the above hydrolytic transformation and/or isomerization, if any, the hydrolyzable group such as 3-acyloxy may be simultaneously decomposed. However, the intended hydrolytic transformation and/ or isomerization are not blocked by this side reaction.

The objective A' -6-oxomorphinan (I) occurs in optically active form as Well as in racemic mixture and these are all within the scope of the present invention.

The A' -6-oxomorphinan (I) forms acid addition salts with organic and inorganic acids. Illustrative acid addition salts include the hydrohalide (e.g. hydrochloride, hydrobromide, hydroiodide), sulfate, phosphate, nitrate, tartrate, salicylate, benzoate, malate, citrate, acetate, etc.

The thus-produced A -6-oxomorphinan (I) and acid addition salts thereof exhibit various pharmacological activities such as analgesic activity and antitussive activity. For instance, the analgesic activity, antitussive activity and toxicity of some A -6-oxomorphinan derivatives according to the present invention are shown in the following table:

TABLE NOTE T11O analgesic activity was observed by the DAinour- Smith method [DAmour et al.: J. Pharmacol, vol. 1, p. 255 (1946)] in rats and is shown as the effective ratio to mor phine, the "nine of which is expressed as 1. The antitussive activity was observed by the Winter method [Winter et al.: J. Exper. Med, vol. 101, p. 17 (1955)] in guinea pigs and is shown as the effective ratio to codeine, the value of which is expressed as 1. The toxicity was tested by the intravenous administration of the tested compound to mice andis shown by LDao (Lethal Dose).

The other A -6-oxomorphinan derivatives of the present invention also show the similar pharmacological activities. Accordingly, they are useful as analgesic and/or antitussive agents.

Practical and presently preferred embodiments of the present invention are illustrated by the following examples. In the examples, abbreviations each have conventional meanings, e.g. mg.=milligram(s), g.= ran1(s),

ml.=millilitre(s), C.=degrees centigrade.

EXAMPLE 1 Preparation of -3-methoxy-6-0x0-N-methyl-A -m0rphinan (cis) and )-3-metlroxy-lS-oxo-N-methyl- N-morphinan (trans) A solution of ()-3,6-dimethoxy-N-methyl-A -morphinan (cis) (2 g.) in 10% potassium bisulfate (40 ml.) is allowed to stand overnight at 18 C. The reaction mixture is made to alkalinity with sodium carbonate and shaken with benzene. The benzene layer is dried and chromatographed on alumina. The first fraction is evaporated and crystallized from ether to give (+)-3- methoxy-6-oxo-N-methyl-A morphinan (trans) (234 mg.) as crystals melting at 123 C. +51.7 (ethanol).

l Analysis.-Calcd. for C H O N: C, 76.26; H, 7.47; N, 4.94. Found: C, 76.68; H, 7.69; N, 5.17.

The second fraction is evaporated and crystallized from ether to give (-)-3-methoxy-6-oxo-N-methyl-A' -morphinan (cis) (268 mg.) as crystals melting at 153 to 154 C. [111, -81.9 (ethanol).

AnaIysis.Calcd. for C H O Nz C, 76.26; H, 7.47; N, 4.94. Found: C, 76.40; H, 7.71; N, 4.68.

The starting material of this example, ()-3,6-dimethoxy-N-methyl-A -morphinan (cis), is a known compound [Sawa et al.: Tetrahedron, vol. 15, p. 154 (1961)].

EXAMPLE 2 Preparation of -3-met/zoxy-6-0x0-N-methyl-N-morphinan (cis) and -3-meth0xy-6-0x0-N-methyl-A morphinan (trans) 1&1

A solution of ()-3,6-dimethoxy-N-methyl-A -morphinan (cis) (2 g.) in 5% hydrochloric acid (10 ml.) is heated on a steam bath for 10 minutes. The reaction mixture is treated as in Example 1 whereby there are obtained )-3 -methoxy-6-oxo-N-methyl-A -morphinan (trans) (429 mg.) as crystals melting at 123 C. and ()-3-methoxy 6-oxo-N-methyl A morphinan (cis) (268 mg.) as crystals melting at 153 C.

EXAMPLE 3 Preparation of ()-3-meth0xy-6-0x0-N-methyl-A morphinan (cis) H IN N-CII O A solution of -3 ,6-dimethoxy-N-methyl-A -morphinan (cis) (1 g.) in acetic acid (10 ml.) is heated on a steam bath for 1 hour. The reaction mixture is CH O 7 .treated as in Example 1 whereby there is obtained EXAMPLE 4 Preparation 0 f -3-methoxy-6-0x0-N-mefl1yl-A morph inan (cis) Preparation of -3-meth0xy-6-0x0-N-me thyl-N- morphinan cis) onto- A mixture of (+)-3-methoxy-6-oxo-N-methyl-A -morphinan (trans) (300 mg.) with 50% acetic acid (3 m1.) is heated on a steam bath for 1 hour. The reaction mixture is treated as in Example 1 whereby there is obtained ()-3-methoxy-6-oxoN-methyl A morphinan (cis) (132 mg.) as crystals melting at 152 to 153 C.

EXAMPLE 6 Preparation of ()-3-meth0xy-4-phenyl0xy-6-0xo-N- methyl-N-morphinan (cis) and (+)-3-meth0xy-4- plzanylxy-6-ox0-N-methyl-n' -morphinan (trans) A solution of (+)-3,6-dimethoxy-4-phenyloxy-N- methyl-A -morphinan (cis) (3.89 g.) in 10% hydrochloric acid (78 ml.) is heated on a steam bathfor minutes. After cooling, the reaction mixture is made to alkalinity with ammonia-Water and shaken with benzene. The benzene layer is washed with water, dried and chromatographed on alumina g.). The eluate (2.96- g.) with benzene is evaporated, treated with ether and filtered. The collected insoluble substance is crystallized from ethanol to give (-|)-3-methoXy-4-phenyloxy-6-oxo- N-methyl-A' 'morphinan (trans) (2.05 g.) as crystals melting at 157 C. +90.7 (chloroform).

Analysis.Calcd. for C H O N: C, 76.77; H, 6.71; N, 3.73. Found: C, 76.93; H, 6.87; N, 3.55.

The methi0dide.M.P., 165 to 166 C. (crystallized from acetone).

The filtrate from which the insoluble substance was separated as above is evaporated. The residue is crystallized from ether saturated with Water to give ()-3- methoxy-4-phenyloxy-6-oxo-N-methyl-A"-morphinan (cis) 6 (96.5 mg.) as crystals melting at 143 C. 12.4 (chloroform) Analysis.Calcd. for C24H2503N'M1H2OI C, H, 6.76; N, 3.69. Found: C, 75.93; H, 6.77; N, 3.30.

The Methi0dide.M.P., 185 C. (dec0mp.) (crystallized from acetone).

The starting material of this example, (+)-3,6-dimethoxy-4-phenyloxy-N-methyl-A -morphinan (cis), is a known compound [Sawa et al.: Tetrahedron, Vol. 15, p. 154 (1961)].

EXAMPLE 7 Preparation of -3-methoxy-4-phenyloxy-6-oxo-N- methyl-A' -morphinan (cis) CH O 011 0- C aH C BEIEO A solution of (+)-3,6-dimethoxy 4 phenyloXy-N- methyl-A -morphinan (cis) (3.89 g.) in cone. hydrochloric acid (40 ml.) is heated on a steam bath for 15 minutes. After cooling, the reaction mixture is made to alkalinity with ammonia and shaken with benzene. The benzene layer is washed with water, dried and chromatographed on alumina (20 g.). The benzene solution is evaporated and crystallized from ether saturated with water to give )-3-methoxy 4 phenyloxy-6-oxo-N- methyl-A' -morphinan (cis) (1.81 g.) as crystals melting What is claimed is:

1. A process for preparing A' -6-oxomorphinan derivatives which comprises treating ()-3,6-dimethoxy-N- methyl-A -morphinan (cis) with potassium bisulfate in an aqueous medium at a temperature from room temperature to reflux temperature, the concentration of the methyl-A -morphinan (cis) with acetic acid in an aque- References Cited by the Examiner UNITED STATES PATENTS 4/1963 Sawa et al. 260285 OTHER REFERENCES Bentley, The Chemistry of the Morphine Alkaloids, p. 302 1954).

Gates et al., I. Am. Chem. Soc., Vol. 75, pp. 379-381 (1953).

Hartung, Ind. Eng. Chem, Vol 37, pp. 126-127 (1945).

NICHOLAS S. RIZZO, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

DON M. KERR, DONALD D. DAUS,

Assistant Examiners. 

2. A PROCESS FOR PREAPRING $7-6-OXOMORPHINAN DERIVATIVES WHICH COMPRISES TREATING (-)-3,6-DIMETHOXY-NMETHYL-$5,8-MORPHINAN (CIS) WITH ACETIC ACID IN AN AQUEOUS MEDIUM AT A TEMPERATURE FROM ROOM TEMPERATURE TO REFLUX TEMPERATURE THE CONCENTRATION OF THE ACETIC ACID BEING ABOUT 50%, TO PRODUCE (-)-3-METHOXY-6-OXO-NMETHYL-$7-MORPHINAN (CIS). 